ABSTRACT Babies born from Zika-infected mothers have an unacceptably high probability of having serious life-altering birth defects, such as microcephaly, and other serious anomalies of the anterior nervous system. However, there is currently no molecular data addressing how Zika infection of a pregnant woman can so drastically alter fetal development. The defects seen in Zika-affected infants are strikingly similar to defects observed in embryos of model organisms where cellular and molecular pathways that drive anterior cell-fate decisions required to form the head and central nervous system have been disrupted. These pathways, including several mechanistically relevant proteins, are highly conserved in all vertebrate organisms. Thus, Zika must alter one or more of these pathways in the earliest stages of embryogenesis and perturb the cell-fate decisions of anterior progenitor cells. We will address this idea in our proposal and test the hypothesis that the Zika virus can directly perturb anterior cell-fate decisions during embryogenesis, either because a Zika-encoded viral protein(s) inhibit an early critical developmental pathway(s) (Aim 1) and/or because Zika directly infects neural progenitor cells at an early stage of embryogenesis (Aim 2). To test our ideas we will exploit the unique experimental advantages of the well-established vertebrate model organism, Xenopus laevis. Experimental evidence supporting our hypothesis will be a major advance in defining how Zika can so severely alter fetal development at the level of molecular mechanism. Such information could prove essential for developing molecular therapeutics to diminish the devastating effect of Zika on future society.